Project Summary (Project 3, Co-PIs: Tsien, Froemke, Buzsaki) Neuromodulators act across many timescales?a consequence of the dynamics of their release, receptor activation and downstream signaling. Their actions target numerous subcellular compartments, shaping synaptic transmission, intrinsic excitability and long-term plasticity. How, in turn, these phenomena translate to behavior is a fundamental goal of neuroscience research. In Project 3, we grapple with this complexity by deconstructing the actions of the peptide and hormone oxytocin. Famous for its roles in the periphery and in social behavior, the biophysical and cellular consequences of oxytocin signaling in the central nervous system are poorly described. A thorough understanding of how oxytocin?s role in the brain is further motivated by disruption of oxytocin signaling in various neuropsychiatric disorders, including ASD and schizophrenia. To address this gap in knowledge, we will study the cellular, synaptic and microcircuit signaling mechanisms of oxytocin in the hippocampus, focusing on the CA2 subregion. Long overlooked, CA2 is enriched in OXTRs and, intriguingly, has been implicated in social behavior. Our most recent efforts have focused on how activation of the OXTR depolarizes CA2 pyramidal cells and causes them to enter into a burst firing mode. This effect was attributable to inhibition of a Kv7-mediated potassium current (or M-current), downstream of a Gq- coupled signaling pathway. In Project 3, we take these biophysical results into increasingly more physiological contexts. In Aim 1, we ask how endogenous activity patterns of oxytocinergic fibers translate into oxytocin release, receptor activation and changes in intrinsic excitability. In Aim 2, we test the strength of our model (in which oxytocin?s effects in the hippocampus are primarily mediated by M-current inhibition), by developing optical tools that test the sufficiency and necessity of M-current inhibition in oxytocin signaling. In Aim 3, we ask how profound changes in hippocampal activity, specifically in CA2, are transmitted beyond the hippocampus. We primarily focus our efforts on the lateral septum; a region long implicated in social behaviors, densely innervated by the hippocampus and rich itself in OXTRs. In sum, we propose a research plan that distills oxytocin signaling in the hippocampus into its most elementary components: peptide release, receptor activation and cell-type specific modulation of the M-current. Then, as an acid test of our understanding, we attempt to reconstruct oxytocin?s modulatory actions using our newly developed optical tools. Finally, we consider how oxytocin signaling in the hippocampus may propagate to downstream structures, ultimately influencing social behavior.